1. Field of the Invention
This invention relates to an apparatus and method for the non-invasive diagnosis of a disease state or the non-invasive determination of concentrations of analytes in vivo.
2. Discussion of the Art
Diabetes mellitus is a chronic systemic disease in which the body either fails to produce or fails to respond to the hormone insulin, which regulates the metabolism of glucose. It is estimated that there are 16 million diabetics in the United States and 100 million diabetics worldwide. The growth rate in the number of diabetics is estimated at 11.5% annually. The number of diabetics is estimated to be as high as 154 million worldwide by the year 2000 (H. King, R. E. Aubert, and W. H. Herman, “Global burden of diabetes, 1995–2025 prevalence, numerical estimates and projections” Diabetes Care 1998;21:1414), and to exceed 200 million worldwide by the year 2010. A large number of diabetics remain undiagnosed. A method for screening for diabetes would be beneficial for early diagnosis and for starting treatment and management well before the onset of complications.
Diabetes is frequently associated with microangiopathy. Microangiopathy results from the effect of diabetes on microcirculation, which involves the small blood vessels such as capillaries, venules, arterioles, and shunts. Microangiopathy can lead to micro-vessel complications such as neuropathy (nerve damage), retinopathy (eye damage), and nephropathy (kidney failure). The expression “diabetic angiopathy” deals with effect of diabetes on the arterial as well as the other elements of the vascular system such as venules, veins, and lymph subsystem. The relationship between diabetes and impaired circulation has been known in the medical art for the past two decades. Laser Doppler flowmetry has been used to diagnose peripheral vascular disease and vascular complications in diabetic patients. Impaired circulation is manifested by a decrease in cutaneous blood flow and a decrease in response to temperature changes, i.e., cooling or warming of the skin.
There is growing evidence that microcirculatory defects can be detected well before detection of fasting hyperglycemia, i.e. high blood glucose level for a fasting subject (N. Wiernsperger, Diabetologia 2000; 43; 1439–1449). Laser Doppler flowmetry and capillary microscopy studies have indicated microcirculation disturbances due to diabetes and have shown differences in cutaneous blood flow between diabetics and non-diabetics (S. B. Wilson, “Detection of microvascular impairment in type 1 diabetes by laser Doppler flowmetry, Clinical Physiology, 1992; 12; 195). In diabetic subjects, heating of a body part, or contralateral cooling of a body part, resulted in impaired blood flow, as measured by laser Doppler flowmetry (M. Rendell et al, “Microvascular blood flow, volume and velocity measurements by laser Doppler techniques in IDDM” Diabetes; 1989: 819–824). However, these studies of capillary blood flow and laser Doppler flowmetry were reported for advanced stages of diabetes (M Rendell et al, “Diabetic cutaneous microangiopathy” American Journal of Medicine 1992; 93: 611). Additionally, X-ray crystallographic studies showed differences in structure of tissues of diabetic subjects, due to cross-linking of collagen fibers resulting from glycation (V. J. James et al., “Use of X-ray Diffraction in Study of Human Diabetic and Aging Collagen”, Diabetes, Vol.40 (1991) 391–394).
Diabetes and certain other diseases cause structural changes to the skin that can affect the optical properties thereof, the response of these optical properties to changes in concentration of glucose or other analytes, and the response of these optical properties to cutaneous temperature changes. R. G. Sibbald et al., “Skin and Diabetes”, Endocrinology and Metabolism Clinics of North America, Vol. 25, No. 2 (1996) 463–472, summarize a set of structural effects of the skin that are associated with diabetes. Included among these effects is thickened skin, which may relate pathophysiologically to accelerated collagen aging, with elastic fiber fraying and increased crosslinking, resulting from glycosylation of collagen fibers. Another effect of diabetes is “yellow skin”, which also results from glycosylation of dermal collagen. Change in dermal collagen structure in diabetic patients has been also reported by V. M. Monnier et al., “Skin Collagen Glycation, Glycoxidation, and Crosslinking Are Lower in Subjects With Long-Term Intensive Versus Conventional Therapy of Type 1 Diabetes”, Diabetes, Vol. 48 (1999) 870–880. Further, V. J. James et al., “Use of X-ray Diffraction in Study of Human Diabetic and Aging Collagen”, Diabetes, Vol. 40 (1991) 391–394, shows that collagen skin fiber undergoes a structural change as a result of diabetes. The net effect of these findings is that there are structural differences, i.e., size, level of crosslinking, and distribution of collagen fibers, in the skin of diabetic subjects as compared with the skin of non-diabetic subjects. These differences result in a difference in the scattering characteristics of the skin of diabetic subjects.
In order to understand the effect of the structural differences between the skin of diabetics and that of non-diabetics on the measured optical signals, it is useful to examine the scattering of light in human tissue.
The scattering of light by human tissue can be approximated by an equation that expresses the reduced scattering coefficient μ′s for a tissue or a turbid medium as:μ′s=3.28πa2ρ(2πanmedium/λ)0.37(m−1)2.09  (1)where “a” represents the average cell diameter, ρ represents the number concentration of cells, “nmedium” represents the refractive index of interstitial fluid, λ represents the wavelength, and m represents the ratio of the refractive index of the cells to that of the interstitial fluid (m=ncells/nmedium). The scattering coefficient changes as cell size “a” or refractive index “nmedium” change. Temperature can affect the scattering coefficient by a change in cell diameter “a”, a change in the number concentration of cells ρ, or a change in the refractive index mismatch “m”. Because the diabetic status is independent of glucose concentration, i.e., a diabetic patient can have high or low blood glucose level, it is possible to assume that the diabetic status is independent of “m”. However, differences in crosslinking of collagen for diabetics may lead to a different range for the dimensional parameter “a” between the diabetic and the non-diabetic groups. Differences in the variable “a” will lead to a difference in the scattering characteristics of the skin of diabetic subjects, because the scattering characteristics affect the term “a” in Equation (1). Thus, the response of the scattering coefficient to changes in glucose concentration, or other concentrations of analytes, and the response of the scattering coefficient to cutaneous temperature changes are expected to be different for diabetic subjects as compared to those responses of the same parameters determined for non-diabetic subjects.
Scattering properties of tissue can vary with temperature as a result of one or more of the following changes:                (a) an increase in temperature can decrease the refractive index of interstitial fluid and increase the scattering coefficient of tissue;        (b) an increase in temperature can change the refractive index of cell membranes;        (c) an increase in temperature can increase cell size, and hence, can increase the scattering coefficient.In the case of (a) or (b), an increase in the refractive index mismatch “m” in Equation (1), which increases as the temperature increases, can also increase the scattering coefficient.        
Methods of diagnosing diabetes typically require a large number of laboratory tests, such as, for example, successive blood glucose level measurements while the patient is in a fasting state, determination of serum glycated hemoglobin HbA1c, and oral glucose tolerance (or meal tolerance) tests. These tests are usually performed after clinical symptoms of diabetes are observed. These symptoms include thirst, fatigue, and frequent urination (Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, Diabetes Care 1997; 20:117–135). The use of a glycated hemoglobin test has been equivocal in diagnosing diabetes, even though it is time-consuming and requires drawing of blood. See C. L. Rohlfing et al., “Use of HbA1c in screening for undiagnosed diabetes in US population”, Diabetes Care 2000; 23: 187–191.
A non-invasive test for screening diabetics will save a great number of laboratory tests and will allow screening larger populations, even if clinical symptoms of diabetes are not evident. A non-invasive test will also allow early diagnosis and subsequent control of diabetes, which in turn will delay the onset of complications from diabetes. If uncontrolled, diabetes can result in a variety of adverse clinical manifestations, including retinopathy, atherosclerosis, microangiopathy, nephropathy, and neuropathy. In its advanced stages, diabetes can cause blindness, coma, and ultimately death.
Non-invasive determination of glucose has been the subject of several patents. U.S. Pat. Nos. 5,082,787; 5,068,536; 5,077,476; 5,086,229; 5,204,532; 5,237,178; 5,362,966 describe transmission measurements through the finger. U.S. Pat. Nos. 5,321,265; and, 5,434,412 describe Kromoscopic methods for the determination of glucose. U.S. Pat. Nos. 5,492,118 and 5,551,422 describe measurements based on light scattering. U.S. Pat. Nos. 4,655,225; 4,882,492; 5,460,177; 4,975,581 describe methods for the detection of glucose with light of long wavelength (>1100 nm) where glucose does, presumably, have stronger absorption bands. U.S. Pat. Nos. 5,009,230; 4,975,581; 5,379,764; 4,655,225; 5,893,364; 5,497,769; 5,209,231; and 5,348,003 describe a variety of optical methods for the non-invasive determination of blood glucose level in the human body.
U.S. Pat. No. 5,362,966 describes measurement of finger temperature away from the optical measurement area. WO 95/04924 describes a near infrared non-invasive measurement instrument, where light is introduced and measured at an extremity, such as a finger tip, while the temperature of the same extremity is measured at another location remote from the location of the optical measurement area. The temperature value measured is used in the calculation algorithm together with the optical data to determine the concentration of an analyte. The temperature at the measurement site is not controlled or varied according to a preset program. U.S. Pat. No. 5,551,422 describes a glucose sensor that is brought to a specified temperature, preferably somewhat above the body normal temperature, with a thermostatically controlled heating system. U.S. Pat. No. 5,666,956 describes a method for the determination of glucose from the infrared emission of the tympanic membrane. U.S. Pat. No. 5,978,691 describes a method of measuring changes in molecular behavior, induced by a change in thermal energy, to facilitate the measurement of physiological parameters in blood.
U.S. Pat. No. 5,844,239 describes a fiber-optics-based optical device for determination of the optical properties at a shallow depth in a tissue. The sensor comprises several unit fiber bundles. Each unit fiber bundle has a light introduction fiber and several light collection fibers arranged in concentric rings. Signals from each group of fibers at the same distance are detected to enhance the signal to noise ratio. Further, signals from the plurality of unit bundles are added up, or averaged, to further improve the signal to noise ratio. The temperature is not controlled at the positions where the unit bundles contact the skin. The temperature is not varied according to a preset program.
U.S. application Ser. No. 09/080,470, filed May 18, 1998, assigned to the assignee of this application, describes a sensor employing a temperature control for non-invasive determination of blood glucose level. U.S. application Ser. No. 09/098,049, filed Nov. 23, 1998, assigned to the assignee of this application, describes methods for determining optical properties of tissue having a plurality of layers non-invasively. Both applications disclose the use of a temperature controllable optical element that contacts the skin.
Cutaneous microcirculation occurs at depths of 1 to 2 mm below the epidermal surface of the skin (I. M. Braverman, “The Cutaneous Microcirculation: Ultrastructure and Microanatomical Organization”, Microcirculation (1997) Vol. 4, No. 3, 329–340). Thus, measurement of optical properties of skin close to the surface thereof can provide useful information on the effect of blood circulation on the concentration of metabolites in tissues that are close to the surface of the skin. Also, studies of blood circulation close to the surface of the skin by means of laser Doppler flowmetry (referred to as LDF herein) have shown that laser Doppler flowmetry is a good tool for diagnosing peripheral circulatory disease. Laser Doppler flowmetry (LDF) measurements are restricted to the top-most layer of the skin (≈200 microns) because the beam loses its coherence due to scattering. Temperature dependence of laser Doppler flowmetry studies does not incorporate structural changes in the skin due to diabetes. Thus, a deficiency in the LDF prior art is the lack of inclusion of temperature dependence of scattering in the classification and diagnosis of diabetes complications.
Although a variety of detection techniques have been disclosed in the art, there is still no commercially available device that provides reliable non-invasive measurements of blood glucose level. As a result, current approaches to non-invasive metabolite testing, such as glucose monitoring, have not achieved wide acceptance.